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Genome mining and gene deletion experiments in Penicillium crustosumproved the involvement of the PKS-NRPS PemA and the trans-enoyl reductase PemB in the formation of three enantiomeric clavatol-containing tetramate pairs. Overexpression of a transcription factor significantly improved the product yields. Feeding experiments provided evidence for their formation via 1,4-Michael addition of hydroxyclavatol to two tetramates from the Pem pathway. This study provides another example of the involvement of reactive intermediates in multiple biosynthetic pathways.

Deficits in impulse control are observed in several neurocognitive disorders, including attention deficit hyperactivity (ADHD), substance use disorders (SUDs), and those following traumatic brain injury (TBI). Understanding brain circuits and mechanisms contributing to impulsive behavior may aid in identifying therapeutic interventions. We previously reported that intact lateral habenula (LHb) function is necessary to limit impulsivity defined by impaired response inhibition in rats. Here, we examine the involvement of a synaptic input to the LHb on response inhibition using cellular, circuit, and behavioral approaches. Retrograde fluorogold tracing identified basal forebrain (BF) inputs to LHb, primarily arising from ventral pallidum and nucleus accumbens shell (VP/NAcs). Glutamic acid decarboxylase and cannabinoid CB1 receptor (CB1R) mRNAs colocalized with fluorogold, suggesting a cannabinoid modulated GABAergic pathway. Optogenetic activation of these axons strongly inhibited LHb neuron action potentials and GABA release was tonically suppressed by an endogenous cannabinoid in vitro. Behavioral experiments showed that response inhibition during signaled reward omission was impaired when VP/NAcs inputs to LHb were optogenetically stimulated, whereas inhibition of this pathway did not alter LHb control of impulsivity. Systemic injection with the psychotropic phytocannabinoid, Δ9-tetrahydrocannabinol (Δ9-THC), also increased impulsivity in male, and not female rats, and this was blocked by LHb CB1R antagonism. However, as optogenetic VP/NAcs pathway inhibition did not alter impulse control, we conclude that the pro-impulsive effects of Δ9-THC likely do not occur via inhibition of this afferent. These results identify an inhibitory LHb afferent that is controlled by CB1Rs that can regulate impulsive behavior.

Senescence, an intricate and inevitable biological process, characterized by the gradual loss of homeostasis and declining organ functions. The pathological features of cellular senescence, including cell cycle arrest, metabolic disruptions, and the emergence of senescence-associated secretory phenotypes (SASP), collectively contribute to the intricate and multifaceted nature of senescence. Beyond its classical interaction with p53, murine double minute gene 2 (MDM2), traditionally known as an E3 ubiquitin ligase involved in protein degradation, plays a pivotal role in cellular processes governing senescence. Histone deacetylase (HDAC), a class of histone deacetylases mainly expressed in the nucleus, has emerged as a critical contributor to renal tissues senescence. In this study we investigated the interplay between MDM2 and HDAC1 in renal senescence. We established a natural aging model in mice over a 2-year period that was verified by SA-β-GAL staining and increased expression of senescence-associated markers such as p21, p16, and TNF-α in the kidneys. Furthermore, we showed that the expression of MDM2 was markedly increased, while HDAC1 expression underwent downregulation during renal senescence. This phenomenon was confirmed in H2O2-stimulated HK2 cells in vitro. Knockout of renal tubular MDM2 alleviated renal senescence in aged mice and in H2O2-stimulated HK2 cells. Moreover, we demonstrated that MDM2 promoted renal senescence by orchestrating the ubiquitination and subsequent degradation of HDAC1. These mechanisms synergistically accelerate the aging process in renal tissues, highlighting the intricate interplay between MDM2 and HDAC1, underpinning the age-related organ function decline.

Targeted delivery systems combined with the stimuli-responsive release of drug molecules hold noteworthy promise for precision medicine, enabling treatments with enhanced effectiveness and reduced adverse effects. An ideal drug delivery platform with versatile targeting moieties, the capability of combinational payloads, and simple preparation is highly desirable. Herein, we developed pH-sensitive fluorescent self-assembled complexes (SACs) of a galactose-functionalized G-quadruplex (G4) and a coumarin carboxamidine derivative as a targeted delivery platform through the nanoprecipitation method. These SACs selectively targeted hepatocellular carcinoma (HepG2) cells in fluorescence imaging after a short incubation and exerted specific anticancer effects in an appropriate dose range. Co-delivery of 1 μM prodrug floxuridine oligomers and 16 μg/mL SACs (minimal hemolytic effect) significantly reduced the cytotoxicity of the nucleoside anticancer drug on normal cells (NIH/3T3), kept up to 70% alive after 72-h incubation, and improved anticancer efficacy compared to SACs alone. This strategy can be extended to ratiometric multidrug delivery through self-assembly for targeted combinational therapy.

Parabens are frequently used preservatives in food and personal care products. These are also termed endocrine disruptors which have the potential to damage the endocrine system Therefore, an easy and facile extraction and detection of parabens are critically important. This work evaluates different magnetic sorbents such as Fe3O4@MIL‐101(Cr), Fe3O4@MIL‐101(Cr)@NH2, and Fe3O4@MIL‐101(Cr)@SO3H for magnetic solid phase extraction (MSPE) and further selected Fe3O4@MIL‐101(Cr)@NH2to determine paraben content in chili powder and facial toner samples. Fe3O4@MIL‐101(Cr)@NH2is an efficient sorbent material specially designed for MSPE, which profoundly extracted nine parabens within a short span of just 6 min, driven by π–π interaction and hydrogen bonding. And a detailed optimization and LC–MS/MS analysis was carried out. Fe3O4@MIL‐101(Cr)@NH2exhibited superior extraction efficiency, enabling subsequent quantification via LC–MS/MS. The limit of detection ranged from 0.063 to 0.622 ng mL−1and limit of quantification of 0.211 to 2.073 ng mL−1were a good recovery in the range of 76.2%–108%. An effective detection of eight parabens in chili powder and four parabens in facial toner samples was determined indicating that Fe3O4@MIL‐101(Cr)‐NH2sorbents are suitable for MSPE.

In 2008, sorafenib became the first approved systemic therapeutic agent for advanced HCC. Although its pharmacological efficacy has been established, reimbursement for such a new, high‐cost drug, as well as physicians' awareness and prescription practice, likewise contribute to its clinical effectiveness. We therefore conducted a retrospective study using 38 sorafenib‐eligible, advanced HCC patients when sorafenib was approved but not yet reimbursed as a control and 216 patients during the reimbursed era. Study group showed longer survival at 8.2 months versus the control's 4.9 months (p= 0.0063 hazard ratio: 0.612 [0.431 ~ 0.868], p= 0.0059). Among the 42 (19.4%) patients who survived more than 2 years, 50% had tumor rupture, and all 32 patients with portal vein tumor thrombus and/or extrahepatic metastasis received sorafenib (p= 0.003). Furthermore, during their first 2 years of HCC management, sorafenib had been given in 29.1% of the treatment courses among survivors between 2 and 5 years while it was prescribed in 55.8% among the more than 5 years survivor group (p< 0.001). In conclusion, survival of sorafenib‐eligible HCC patients significantly improved after reimbursement. Patients who underwent longer sorafenib treatment had a survival advantage, except for those with tumor rupture. Reimbursement and awareness of prescriptions for a newly introduced medication therefore improve clinical effectiveness.

Study design Single centre, cross-sectional study.Objectives The objective is to report the prevalence of spondylolisthesis and retrolisthesis, analyse both conditions in terms of the affected levels and severity, as well as identify their risk factors.Methods A review of clinical data and radiographic images of consecutive spine patients seen in outpatient clinics over a 1-month period is performed. Images are obtained using the EOS® technology under standardised protocol, and radiographic measurements were performed by 2 independent, blinded spine surgeons. The prevalence of both conditions were shown and categorised based on the spinal level involvement and severity. Associated risk factors were identified.Results A total of 256 subjects (46.1% males) with 2304 discs from T9/10 to L5/S1 were studied. Their mean age was 52.2(± 18.7) years. The overall prevalence of spondylolisthesis and retrolisthesis was 25.9% and 17.1% respectively. Spondylolisthesis occurs frequently at L4/5(16.3%), and retrolisthesis at L3/4(6.8%). Majority of the patients with spondylolisthesis had a Grade I slip (84.3%), while those with retrolisthesis had a Grade I slip. The presence of spondylolisthesis was found associated with increased age (P< .001), female gender (OR: 2.310; P= .005), predominantly sitting occupations (OR:2.421; P= .008), higher American Society of Anaesthesiology grades (P= .001), and lower limb radiculopathy (OR: 2.175; P= .007). Patients with spondylolisthesis had larger Pelvic Incidence (P< .001), Pelvic Tilt (P< .001) and Knee alignment angle (P= .011), but smaller Thoracolumbar junctional angle (P= .008), Spinocoxa angle (P= .007). Retrolisthesis was associated with a larger Thoracolumbar junctional angle (P=.039).Conclusion This is the first study that details the prevalence of spondylolisthesis and retrolisthesis simultaneously, using the EOS technology and updated sagittal radiographic parameters. It allows better understanding of both conditions, their mutual relationship, and associated clinical and radiographic risk factors.

Century eggs (also known as pídàn) are a widely used preserved food product in Taiwanese cuisine. Due to their peculiar appearance, pungent odor, and unusual texture, several consumers have raised concerns. Actually, some metallic additives are employed to control the quality of gelation of protein during the production of century eggs. Therefore, a method involving microwave plasma‐atomic emission spectrometer and microwave‐assisted digestion was proposed in this study. In addition, to clarify distribution information of metallic additives in century eggs, detailed analyses based on the egg structure were adopted. The linearities for Fe and Zn were obtained in the range of 0.1–5, and 0.02–1 mg L−1for Cu and Pb. The method detection limits for test metals were 0.06–0.036 mg L−1. The measured values for the RM EGGS‐1 sample agreed reasonably well with the reference values, demonstrating that the developed method is practical for routine analysis with lower instrument procurement/running cost. The analytical results for century eggs collected from local markets revealed diverse distributions of metal ions in different parts. Remarkably, this method can readily identify the metallic additives used during the production processes even in the presence of complicated matrices. Because metallic additives are widely employed to control protein gelation during the production of century eggs, quantitative information regarding these additives is crucial for ensuring the safe consumption of century eggs. The developed methodology can not only identify such additives during the production processes but also clearly indicate the distribution of metal ions in century eggs.

Productivity of tropical and subtropical grasslands is often limited by inadequate nitrogen (N) supply. Aeschynomene (Aeschynomene americanaL.) is a warm‐season legume that may contribute as N input in grazing systems, but there is limited information about aeschynomene litter decomposition and N dynamics on pastures. The objective of this study was to quantify the effect of overseeding aeschynomene or applying N fertilizer to existing bahiagrass (Paspalum notatumFlüggé) on litter disappearance and decomposition rates. The study was conducted in Ona, FL, from October 2019 to May 2020 and October 2020 to May 2021. Treatments were the split‐plot arrangement of bahiagrass‐aeschynomene or bahiagrass monoculture (main plot) and N fertilization level, (0 [control] or 60 kg N ha−1) as subplot, distributed in a randomized complete block design with four replicates. The nylon bag technique was used to estimate organic matter (OM), N and carbon (C) disappearance, and lignin concentration for 184 days of incubation. Bahiagrass‐aeschynomene had greater OM disappearance (from 330 to 356 g kg−1OM) and was driven by C disappearance. Nitrogen fertilization did not impact litter decomposition responses, except for C:N ratio. Overseeding aeschynomene is an effective management practice to increase OM decomposition and optimize nutrient cycling in warm‐season pastures. Overseeding aeschynomene into bahiagrass increased organic matter and N disappearance litter decomposition.Nitrogen fertilization did not affect bahiagrass‐aeschynomene litter decomposition.Bahiagrass‐aeschynomene litter supported soil N mineralization.

Human amniotic membranes (hAMs) are widely used as wound management biomaterials, especially as grafts for corneal reconstruction due to the structure of the extracellular matrix and excellent biological properties. However, their fragile nature and rapid degradation rate hinder widespread clinical use. In this work, we engineered a novel self-powered electronic dress (E-dress), combining the beneficial properties of an amniotic membrane and a flexible electrical electrode to enhance wound healing. The E-dress displayed a sustained discharge capacity, leading to increased epidermal growth factor (EGF) release from amniotic mesenchymal interstitial stem cells. Live/dead staining, CCK-8, and scratch-wound-closure assays were performed in vitro. Compared with amniotic membrane treatment alone, the E-dress promoted cell proliferation and migration of mouse fibroblast cells and lower cytotoxicity. In a mouse full-skin defect model, the E-dress achieved significantly accelerated wound closure. Histological analysis revealed that E-dress treatment promoted epithelialization and neovascularization in mouse skin. The E-dress exhibited a desirable flexibility that aligned with tissue organization and displayed maximum bioactivity within a short period to overcome rapid degradation, implying great potential for clinical applications.

The first direct catalytic asymmetric Mannich reaction of 2-alkylazaarenes and ketimines was realized with a chiral Cu–bis(oxazoline) complex as the catalyst. The asymmetric addition of 2-alkylpyridines to isatin-derived ketimines proceeded smoothly to afford α,β-functionalized 2-substituted pyridines bearing 3-amino-3,3-disubstituted oxindole motifs with excellent results (≤99% yield, 99:1 dr, and 98% ee). The catalytic system was also extended to 2-alkylbenzothiazoles as nucleophiles for the asymmetric Mannich reaction of ketimines.

School practitioners’ receptivity to reform influences the success of policy implementation. In Taiwan, the Ministry of Education launched a curriculum reform in 2019. To determine how to enhance school agency for the policy, we explored the individual and contextual factors affecting receptivity to the new curriculum. With a survey design, this study recruited secondary school teachers and principals throughout Taiwan as samples. Hierarchical regression models were conducted to examine the effects of individual factors (conceptions of distributed leadership and collective learning) and organizational culture (power distance, uncertainty avoidance, and academic emphasis) on practitioners’ receptivity to curriculum reform. Both the main and interactive effects were investigated. The results indicate that respondents who positively conceived distributed leadership and collective learning were more receptive to change. Regarding the three indicators of organizational culture, we found no significant effect of power distance, while the main effect of uncertainty avoidance and the moderation effect of academic emphasis existed. Those who perceived their schools with high uncertainty avoidance levels were more resistant to reform efforts. Besides, a positive linkage between teacher conception of collective learning and affection for change was more evident in schools with less academic emphasis. Our study suggests that school reforms must be understood within the individual and school contexts. The finding about the moderation effect of academic emphasis furthermore signifies the cultural implication in Asian societies.

Astrocyte-derived IL-3 activates the corresponding receptor IL-3Rα in microglia. This cross-talk between astrocytes and microglia ameliorates the pathology of Alzheimer’s disease in mice. In this study we investigated the role of IL-3/IL-3Rα cross-talk and its regulatory mechanisms in ischemic stroke. Ischemic stroke was induced in mice by intraluminal occlusion of the right middle cerebral artery (MCA) for 60 min followed by reperfusion (I/R). Human astrocytes or microglia subjected to oxygen-glucose deprivation and reoxygenation (OGD/Re) were used as in vitro models of brain ischemia. We showed that both I/R and OGD/Re significantly induced decreases in astrocytic IL-3 and microglial IL-3Rα protein levels, accompanied by pro-inflammatory activation of A1-type astrocytes and M1-type microglia. Importantly, astrocyte-derived VEGFD acting on VEGFR3 of astrocytes and microglia contributed to the cross-talk dysfunction and pro-inflammatory activation of the two glial cells, thereby mediating neuronal cell damage. By using metabolomics and multiple biochemical approaches, we demonstrated that IL-3 supplementation to microglia reversed OGD/Re-induced lipid metabolic reprogramming evidenced by upregulated expression of CPT1A, a rate-limiting enzyme for the mitochondrial β-oxidation, and increased levels of glycerophospholipids, the major components of cellular membranes, causing reduced accumulation of lipid droplets, thus reduced pro-inflammatory activation and necrosis, as well as increased phagocytosis of microglia. Notably, exogenous IL-3 and the VEGFR antagonist axitinib reestablished the cross-talk of IL-3/IL-3Rα, improving microglial lipid metabolic levels via upregulation of CPT1A, restoring microglial phagocytotic function and attenuating microglial pro-inflammatory activation, ultimately contributing to brain recovery from I/R insult. Our results demonstrate that VEGFD/VEGFR3 signaling contributes to the dysfunction of the astrocyte IL-3/microglia IL-3Rα cross-talk and drives pro-inflammatory activation, causing lipid metabolic reprogramming of microglia. These insights suggest VEGFR3 antagonism or restoring IL-3 levels as a potential therapeutic strategy for ischemic stroke.

Graphical Abstract: Graphical Abstract: Flexible surface acoustic wave technology for enhancing transdermal drug delivery

In this paper, we propose an alternating proximal gradient algorithm for solving nonsmooth nonconvex-linear minimax problems with coupled linear constraints, which have attracted wide attention in machine learning, signal processing and many other fields in recent years. The iteration complexity of the proposed algorithm is proved to be Oε-3to reach an ε-stationary point. To our knowledge, this is the first algorithm with iteration complexity guarantee for solving nonsmooth nonconvex-linear minimax problems with coupled linear constraints.

The corrosion behavior of an Al0.75CoFeCr1.25Ni high-entropy alloy (HEA) in 0.5 mol/L NaOH solution was investigated using a series of electrochemical and analytical techniques, including X-ray photoelectron spectroscopy, X-ray diffraction, scanning electron microscopy, potentiodynamic polarization measurement and electrochemical impedance spectroscopy. The results showed that the Al0.75CoFeCr1.25Ni HEA exhibited a typical columnar dendritic structure, which is composed of face-centered cubic, body-centered cubic (BCC), and ordered BCC phases (B2 phase). The corrosion resistance of this HEA in 0.5 mol/L NaOH solution is comparable to that of 304 SS, attributed to the change in the composition of the passive film formed on the surface. Although the passive film formed was generally rich in Al, the proportion of Cr2O3inside it increased with the increasing immersion time, enhancing the stability of the passive film and thus improving the corrosion performance of this HEA in 0.5 mol/L NaOH solution.

4-Tertiary-octylphenol (4-t-OP), a frequently utilized alkylphenol, is extensively utilized in a wide range of consumer goods. While experimental research has demonstrated that 4-t-OP exposure leads to increased oxidative stress, it remains unclear if this also occurs in human beings. To investigate this issue, we enrolled 886 Taiwanese adolescents and young adults (aged 12–30 years) and examined the associations among serum 4-t-OP levels, urine oxidized nucleoside 8-hydroxydeoxyguanosine (8-OHdG) (a biomarker of DNA damage), and 8-iso prostaglandin F2α (8-isoPGF2α) (a biomarker of lipid peroxidation). In linear regression analyses, a 1-unit increase in natural log serum 4-t-OP levels was positively associated with urine levels of the 8-OHdG and 8-isoPGF2α (β= 0.083, SE= 0.037, P= 0.025, and β= 0.418, SE= 0.068, P< 0.001) after controlling for covariates. Furthermore, we observed an interaction between age and 4-t-OP, as well as between low-density lipoprotein cholesterol and 4-t-OP, in the association between 4-t-OP and 8-isoPGF2α. In conclusion, our study showed that serum concentrations of 4-t-OP exhibit positive connections with biomarkers of oxidative stress on DNA and lipids. Additional investigation is crucial to determine the presence of a causal link between 4-t-OP exposure and oxidative stress in human subjects.

As the protective component, steel plate had attracted extensive attention because of frequently threats of explosive loads. In this paper, the evolution of microstructure and the mechanism of damage in the quasi-cracking area of steel plate subjected to explosive load were discussed and the relationships between micro defects and dynamic mechanical response were revealed. After the explosion experiment, five observation points were selected equidistant from the quasi-cracking area of the section of the steel plate along the thickness direction, and the characteristics of micro defects at the observation points were analyzed by optical microscope (OM), scanning electron microscope (SEM) and electron back-scattered diffraction (EBSD). The observation result shows that many slip bands (SBs) appeared, and the grain orientation changed obviously in the steel plate, the two were the main damage types of micro defects. In addition, cracks, peeling pits, grooves and other lager micro defects were appeared in the lower area of the plate. The stress parameters of the observation points were obtained through an effective numerical model. The mechanism of damage generation and crack propagation in the quasi-cracking area were clarified by comparing the specific impulse of each observation point with the corresponding micro defects. The result shows that the generation and expansion of micro defects are related to the stress area (i.e. the upper compression area, the neutral plane area, and the lower tension area). The micro defects gather and expand at the grain boundary, and will become macroscopic damage under the continuous action of tensile stress. Besides, the micro defects at the midpoint of the section of the steel plate in the direction away from the explosion center (i.e. the horizontal direction) were also studied. It was found that the specific impulse at these positions were much smaller than that in the thickness direction, the micro defects were only SBs and a few micro cracks, and the those decreased with the increase of the distance from the explosion center.

To evaluate the diagnostic efficacy of contrast‐enhanced ultrasonography (CEUS) for detecting catheter‐related right brachiocephalic vein (RBV) and superior vena cava (SVC) obstructions in patients undergoing hemodialysis (HD). From June 1, 2021 to December 31, 2022, we enrolled 80 patients undergoing HD who had used or were using a central venous catheter as vascular access. We evaluated the diagnostic efficacy of conventional ultrasonography and CEUS for identifying RBV and SVC obstructions and compared them with that of digital subtraction angiography (DSA). In the stratified analysis, the SVC was divided into the upper and lower segments. In total, we analyzed 240 central venous segments, including the RBV. Among the RBV and SVC visualized by DSA, conventional ultrasonography and CEUS could visualize 67.92 and 100% of the vein segments, respectively; however, the lengths and diameters of the RBV and SVC were smaller than those recorded with DSA (P< .001). The diagnostic efficacy of CEUS for detecting catheter‐related central venous obstruction was better than that of conventional ultrasonography, with a higher sensitivity (83.95 vs 41.98%), specificity (89.94 vs 53.46%), accuracy (87.92 vs 49.58%), and F1 score (82.42 vs 49.64%). CEUS showed good agreement (κ= 0.732) with DSA. In the stratified analyses, CEUS also showed higher sensitivity (83.93, 83.33, and 84.62%, respectively) and better agreement with DSA (κ =0.635, 0.655, and 0.673, respectively) than conventional ultrasonography for detecting the RBV and the upper and lower segments of the SVC. CEUS had high sensitivity and specificity in diagnosing catheter‐related RBV and SVC obstructions.

A photocatalytic three-component reaction of a nitroarene, a thiophenol, and a ketone for the synthesis of multifunctional diaryl sulfides was reported using a nitro group as the nitrogen source and thiophenol as the sulfur source. Thiophenol also serves as a proton donor to reduce nitroarene to arylamine as a key intermediate for the formation of C–N and C–S bonds. Good functional group tolerance and mild reaction conditions make this method have practical synthetic value for diversified multifunctional diaryl sulfides.

In recent years, researches on improving high-voltage performance of lithium-ion batteries incorporating LiNi0.5Co0.2Mn0.3O2(NCM523) and artificial graphite (AG) have been widely reported. However, limited attentions have been paid to understand the effects and influence mechanisms of charge and discharge rates and charge limit currents on cyclability of NCM523/AG cells. Herein, a ∼1.9 Ah NCM523/AG pouch cell is employed, whose electrochemical and structural evolutions after 800 cycles at various rates are comprehensively investigated. We find that cycling performances are strongly influenced by charge rate, followed by limit current and discharge rate. The cell charged at a high rate and cell charged until reaching a low limit current both exhibit low capacity retentions compared to the cell discharged at a high rate. Possible failure reasons are analyzed by advanced characterizations. Results reveal that NCM523 cathodes of the cells deteriorated early experience severe transition metal dissolution, lattice distortion, and partial phase transformation. Meanwhile, the deposited transition metals on AG anodes catalyze the electrolyte consumption, lithium plating and active area loss. Finally, these side reactions notably increase cell impedance and electrochemical polarization. Undoubtedly, these findings clearly outline the challenges and optimization direction for high-rate NCM523/AG cells.

This study aimed to investigate the prevalence characteristics of human papillomavirus (HPV) infections in 29,508 female cases in Jinshan District, Shanghai.